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Signal Transduction and Targeted Therapy Feb 2024Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15a PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.
Topics: Humans; Animals; Mice; MicroRNAs; Fos-Related Antigen-2; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; TOR Serine-Threonine Kinases; Tumor Microenvironment; Receptor, IGF Type 1
PubMed: 38342897
DOI: 10.1038/s41392-024-01740-4 -
Cancer Research Communications Feb 2024In pancreatic ductal adenocarcinoma, the infiltration of CD8+ T cells within the tumor microenvironment correlates with a favorable prognosis. However, a significant...
UNLABELLED
In pancreatic ductal adenocarcinoma, the infiltration of CD8+ T cells within the tumor microenvironment correlates with a favorable prognosis. However, a significant proportion of tumor-infiltrating T cells become trapped within the desmoplastic stroma and lack tumor reactivity. Here, we explored different T-cell subsets in pancreatic tumors and adjacent tissues. We identified a subset of CD8+ T cells, double positive (DP) for CD39 and CD103 in pancreatic tumors, which has recently been described to display tumor reactivity in other types of solid tumors. Interestingly, DP CD8+ T cells preferentially accumulated in central tumor tissues compared with paired peripheral tumor and adjacent non-tumor tissues. Consistent with an antigen encounter, DP CD8+ T cells demonstrated higher proliferative rates and displayed an exhausted phenotype, characterized by elevated expression of PD-1 and TIM-3, compared with CD39-CD103- CD8+ T cells. In addition, DP CD8+ T cells exhibited higher expression levels of the tissue trafficking receptors CCR5 and CXCR6, while displaying lower levels of CXCR3 and CXCR4. Importantly, a high proportion of DP CD8+ T cells is associated with increased patient survival. These findings suggest that DP CD8+ T cells with a phenotype reminiscent of that of tumor-reactive T cells are present in pancreatic tumors. The abundance of DP CD8+ T cells could potentially aid in selecting patients for pancreatic cancer immunotherapy trials.
SIGNIFICANCE
Patients with pancreatic cancer with a high proportion of CD39+CD103+ CD8+ T cells exhibiting a tumor-reactive phenotype have improved survival rates, suggesting their potential utility in selecting candidates for immunotherapy trials.
Topics: Humans; CD8-Positive T-Lymphocytes; T-Lymphocyte Subsets; Prognosis; Pancreatic Neoplasms; Phenotype; Tumor Microenvironment
PubMed: 38335302
DOI: 10.1158/2767-9764.CRC-23-0405 -
Annals of Medicine and Surgery (2012) Feb 2024Medulloblastomas are the most common malignant intra-axial brain tumour in paediatric patients and represent 35-40% of posterior fossa tumour types in children between 3...
INTRODUCTION AND IMPORTANCE
Medulloblastomas are the most common malignant intra-axial brain tumour in paediatric patients and represent 35-40% of posterior fossa tumour types in children between 3 and 9 years of age. Medulloblastomas may also be found in adulthood. These tumours are classified into two groups according to its molecular characteristics and histological type. The desmoplastic/nodular subtype is the second common subtype after the classic one. Only three cases of desmoplastic/nodular extra-axial medelloblastoma have been previously reported in the literature originating from to the cerebellopontine angle.
CASE PRESENTATION
The authors report a new case of an extra-axial desmoplastic/nodular cerebellar medulloblastoma originating outside the cerebellopontine angle and mimicking a solitary cerebellar metastasis in a 49-year-old female patient who presented for a raised intracranial pressure and cerebellar syndrome.
CLINICAL DISCUSSION
Medulloblastoma is a malignant embryonal intra-axial tumour of the cerebellum or posterior brain stem that occurs mainly in children. Medulloblastomas may also be found in adulthood. Desmoplastic/nodular medulloblastoma is the second most common type of all medulloblastomas. The intra-axial form is always predominant. Only three cases of extra-axial desmoplastic/nodular medulloblastoma have been reported in the literature. The authors will go through the literature to dissect this rare entity.
CONCLUSION
Although considered a common paediatric intra-axial tumour, there are increasing numbers of solitary cases reporting an extra-axial presentation in different locations of the posterior cerebral fossa even in adulthood. These rare and unusual presentations and locations may mislead the correct diagnosis and delay treatment.
PubMed: 38333306
DOI: 10.1097/MS9.0000000000001617 -
International Journal of Surgical... Feb 2024Various clinicopathological, radiological, and molecular parameters are predictive of prognosis in patients with colorectal carcinoma and distant organ metastases...
Various clinicopathological, radiological, and molecular parameters are predictive of prognosis in patients with colorectal carcinoma and distant organ metastases continue to have a significant place among them. Recent studies reveal that not only the presence of metastases but also the histopathological growth pattern of the metastatic tumor significantly affects prognosis. This study aimed to investigate the prognostic significance of the histopathological growth patterns of metastatic tumors, the morphological findings in the peritumoral non-neoplastic liver, and its relationship with survival in patients who have metastatic colorectal carcinoma. Hematoxylin and eosin-stained slides of the tumors were re-examined in terms of histopathological diagnosis, growth pattern, presence and degree of peritumoral lymphocytic infiltration, steatosis, cholestasis, and peritumoral ductular reaction in the non-neoplastic liver. In terms of histopathological growth patterns, 24 (47%) tumors showed replacement, 19 (37%) showed desmoplastic and 8 (16%) showed pushing growth pattern. In terms of total survival, there was a significant difference ( = .011) between desmoplastic and replacement growth patterns, and the survival period was shorter in patients with replacement growth patterns. Recent studies show that histopathological growth patterns in metastatic liver tumors may be a promising prognostic and predictive parameter. It is important to include this parameter in the pathology reports as it does not require additional equipment for evaluation in routine pathology practice, does not bring additional costs, or takes a long time to evaluate. This feature can be evaluated standardly by every pathologist.
PubMed: 38332662
DOI: 10.1177/10668969241226702 -
Journal of Hematology & Oncology Feb 2024It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and...
BACKGROUND
It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma.
METHODS
RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70 tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs.
RESULTS
In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70 tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70 tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner.
CONCLUSIONS
We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70 cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.
Topics: Humans; Animals; Mice; Cytotoxicity, Immunologic; Interleukin-15; Cancer-Associated Fibroblasts; Cell Line, Tumor; Killer Cells, Natural; Immunotherapy, Adoptive; Lymphoma; Cytokines; CD27 Ligand
PubMed: 38331849
DOI: 10.1186/s13045-024-01525-w -
Cancer Drug Resistance (Alhambra,... 2024The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the... (Review)
Review
The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3β in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.
PubMed: 38318525
DOI: 10.20517/cdr.2023.84 -
Clinical Case Reports Feb 2024Palmar congenital nevus with sclerodermoid reaction has not been reported. It has the potential of deep extension following the fibrous bundle. The utilization of slow...
Palmar congenital nevus with sclerodermoid reaction has not been reported. It has the potential of deep extension following the fibrous bundle. The utilization of slow Mohs or frozen sections with immunohistochemistry staining was recommended.
PubMed: 38314193
DOI: 10.1002/ccr3.8241 -
Journal of Oral and Maxillofacial... 2023Spindle cell lesions comprise a vast plethora of benign and malignant lesions with similar clinical and radiographic features. Their overlapping histopathologic features...
CONTEXT
Spindle cell lesions comprise a vast plethora of benign and malignant lesions with similar clinical and radiographic features. Their overlapping histopathologic features ensure a diagnostic dilemma.
AIM
The current multicentric study aims to delineate fibroblastic and myofibroblastic oral spindle cell lesions based on cytomorphology and comprehensive immunohistochemical analysis.
SETTINGS AND DESIGN
The experimental study was conducted at MS Ramaiah University of Applied Sciences, Bangalore, and All India Institute of Applied Sciences, Delhi.
METHODS AND MATERIAL
A comprehensive histological scoring criteria and panel of immunohistochemical makers (STAT6, CD31, CD34, S100, SMA, vimentin, pan-CK, HHF-35, Ki67, ALK, desmin, HMB-45, SATB2, ERG, EMA and CD99) were employed concurrently for the first time for fibroblastic and myofibroblastic oral spindle cell lesions. The data obtained was tabulated and studied.
STATISTICAL ANALYSIS USED
Results: Using cytological scoring criteria and panel of immunohistochemical makers, the cases analysed and characterized were desmoplastic fibroma, fibrosarcoma, leiomyosarcoma, nodular fasciitis, neurofibroma and epithelioid inflammatory myofibroblastic sarcoma (EIMS).
CONCLUSIONS
The diagnostic strategies need to be upgraded for the diagnosis of spindle cell lesions. Emphasis must be placed on cytomorphology, an immunohistochemistry (IHC) panel of markers is imperative for the accurate diagnosis of fibroblastic and myofibroblastic oral spindle cell lesions.
PubMed: 38304501
DOI: 10.4103/jomfp.jomfp_282_23 -
Asian Journal of Surgery Apr 2024
Topics: Humans; Desmoplastic Small Round Cell Tumor; Biomarkers, Tumor
PubMed: 38296682
DOI: 10.1016/j.asjsur.2024.01.038 -
International Journal of Surgery Case... Feb 2024Medulloblastoma in adults is a rare and highly aggressive central nervous system (CNS) tumor, representing less than 1 % of all brain tumors. Supratentorial metastasis...
INTRODUCTION AND IMPORTANCE
Medulloblastoma in adults is a rare and highly aggressive central nervous system (CNS) tumor, representing less than 1 % of all brain tumors. Supratentorial metastasis is uncommon, and extra-neural metastasis occurs in approximately 5 % of cases, primarily in frontal and temporal lobes. Here, we present an exceptional case of parietal lobe metastasis in an adult with desmoplastic/nodular medulloblastoma. To explore prior cases and establish the uniqueness of our case, we conducted a thorough search on the PubMed database.
CASE PRESENTATION
A 46-year-old male, who was previously treated for medulloblastoma with surgery and adjuvant chemoradiotherapy seven years ago, presented with clinical symptoms suggestive of potential tumor recurrence. Despite two years of dedicated adjuvant chemoradiotherapy, the patient exhibited progressive right hemiparesis, ataxia, and gait disturbances. Subsequent brain magnetic resonance imaging (MRI) revealed a distinct 6 × 4 × 2 cm lesion in the left parietal lobe, which, upon post-operative histopathological examination, was identified as a supratentorial metastasis originating from desmoplastic/nodular medulloblastoma.
CLINICAL DISCUSSION
Medulloblastomas, once categorized as primitive neuroectodermal tumors (PNET), are now distinctly classified as high-grade embryonal tumors, mainly characterized by their histological features and cellular origin. Common clinical presentations include hydrocephalus, headache, unsteady gait, and truncal ataxia. Surgical intervention aims for radical excision, complemented by vital adjuvant chemoradiotherapy to minimize recurrence risk.
CONCLUSION
Considering the possibility of tumor recurrence or intracranial metastasis in patients with medulloblastoma is crucial. Therefore, regular follow-ups are strongly recommended to promptly detect any signs of reoccurrence in these atypical presentations.
PubMed: 38281381
DOI: 10.1016/j.ijscr.2024.109322